SA99200474B1 - benzoylguanidine derivatives - Google Patents

Abstract

Abstract: The present invention relates to novel benzoylguanidine derivatives of general formula I useful for the treatment or reduction of tissue damage caused by ischaemia.

Description

Y

Benzoylguanidine derivatives

BENZOYLGUANIDINE DERIVATIVES

Full description 2 General description of the invention benzoylguanidine derivatives The present invention relates to new pharmaceuticals benzoylguanidine derivatives and methods for the production and use of these compounds in the form of pharmaceutical compositions benzoylguanidine derivatives The first aspect of the invention provides new benzoylguanidine derivatives 1 with the formula 0 ot

AA

NH; a z 0) where b denotes alky live 1 and lamin; alkyl group branched or unbranched cycloalkyl group ollah 01”; Alkoxy group7.,© Cpalkoxy branched or unbranched; NH group; or amino group primary or secondary (secondary) trifluoromethyl group or nitro sii halogen cyano group cyano group 0 v

Cra One or more of the Soy group kylin is devoid of substituents or carries a branched or unbranched aryl aryl; alkoxy-,,0-la «male-,.,© branched or unbranched; primary or secondary alkyl; trifluoromethyl amino group or amino group NH, halogen group (nitro cyano group cyano chydroxy group trifluoromethyl may 5- or 6-membered heteroaryl aryl mixed with five or six members ic sana or 1108 ° choose from heteroatoms containing one atom; two three four or five identical or different atoms sulfur and sulfur oxygen cnitrogen Nitrogen “different” is devoid of substituents or carries one or more substituents in the partial structure alkylaryl an alkyl aryl of the alkyl-benoleic group or alkyl and/or alkyl aryl of the aryl partial structure 1 or NH, branched; unbranched; unbranched Cpy-alkoxy Cru nS < I group; trifluoromethyl group dc gana primary; secondary; amino group amino group .halogen Or halogen nitro cyano group of compounds in formula 1 or its salts tautomers alternating groups Lay The invention includes pharmacologically acceptable salt yo . The preferred compounds for the purposes of the present invention are compounds of the formula General 1 where bearing phenyl without substituents or a phenyl ring may denote an R phenyl ring, trifluoromethyl, trifluoromethyl, or a fluorine substituent of a fluorine group. Anza0rum or methoxy group or pyrrolyl group © x o 83 The following compounds are particularly preferred:

¢?-(;-(7-pyrrolylcarbonyl)-1-piperazinyl)-”-trifluoromethyl-benzoylguanidinemethane 4-(2-pyrrolylcarbonyl)-I-piperazinyl)-1 -piperazinyl)-3- trifluoromethyl-benzoyl )-4 guanidine methanesulphonate 8 " H B Mr Sor A Nm0 L Rh © 0 4-(;-(?-fluorophenylcarbonyl)-1-piperazinyl)-3- Trifluoromethyl-benzoylguanidine Aa sulfonate 4-(4-(4-fluorphenylearbonyl)-I-piperazinyl)-1-piperazinyl)-3- trifluoromethyl-benzoyl guanidine methanesulphonate Fp 0 WU: The subscript Ni ha Zr “1 a 8 - 0 indicates alkyl chlorine or alkyl Cig first.” It usually contains a hydrocarbon group, branched or unbranched, containing 1 hydrocarbon Ve. These include carbon atoms or A atoms, which may optionally carry a Tasty substitute or more than one or more halogen atoms, preferably fluorine, which may be the same or different from each other. the following for example: emethyl cethyl and propyl 1-methylethyl ¢(isopropyl), Vo n-butyl (N-butyl); 1-Methylpropyl JY <l-methylpropyl propyl 011 «2-methylpropyl-dimethylethyl ¢1,1-dimethylethyl 1»pentyl-methylbutyl ¢1-methylbutyl ?-methyl 2-methylbutyl ?-methylbutyl-1011 ¢3-methylbutyl

° Dimethylpropyl 0 < 1,1-dimethylpropyl 7-DiJie propyl “¢1,2-dimethylpropyl 707-dimethylpropyl” 2,2dimethylpropyl 1-ethylpropyl Cl-ethylpropyl hexyl 1-methylpentyl ¢1-methylpentyl 7-methylpentyl “2-methylpentyl 7-methylpentyl” 3-methylpentyl 4-methylpentyl Jie YANTH-011 4-methylpentyl butyl ONTA1L -1,1” SEY) 0 biocell instance | Appendix 1,2-410 10 7-Dimethylbutyl (1,3-dimethylbutyl 717-Dimethyl Jism 2,2-dimethylbutyl 7 7-Dimethylbutyl JETT 2,3-dimethylbutyl) ¢3,3-dimethylbutyl 1-ethyl-butyl Cl-ethylbutyl 7-ethylbutyl 1700 2-ethylbutyl 7-trimethylpropyl YeYeY ¢1,1,2-trimethylpropyl-tri-Jie 1-propyl “1,2,2-trimethylpropyl ethyl-1-methyl propyl L-ethyl-1-methyl propyl and 1-ethyl-7-methylpropyl l-ethyl-2- . methylpropyl Ve Unless otherwise indicated, the preferred hydrocarbon groups are lower alkyl alkyl groups with carbon atoms ranging from 1 to atoms such as methyl ethyl cethyl propyl “propyl ¢ iso-propyl p-butyl n-butyl 1-methylpropyl ¢l-methylpropyl 2-methylpropyl or 10-dimethyl .1,1-dimethylethyl Jus Sale Alkoxy on a straight-chained or branched alkyl group linked via an oxygen atom of 00. Preferably ic gana low molecular weight alkoxy lower alkoxy containing from one atom to ; Carbon atoms, and the methoxy group is particularly preferred. And aryl abh Sale denotes an aromatic group containing from 1 to 10© lamcarbon atoms in that compositions in which the aromatic group may carry one or more substituents of low alkyl groups molecular weight; trifluoromethyl groups (calc sana calkoxy nitro amino groups) and/or one or more halogen atoms; may be similar or different; The preferred aryl group is de gana phenyl bearing the Yo substituents while the preferred substituents are halogen 1410860 (Jie fluorine | 8.4

:: Chlorine or bromine, cbromine, cyano, and hydroxyl, and for the purposes of the present invention, fluorine is the preferred halogen. In addition, the aryl substituent RH - preferably phenyl 160M - may be replaced by a five- or six-membered mixed heteroaryl aryl group that may contain a single hetero-atom; two atoms three; Four or five ° atoms chosen from the group that includes nitrogen, cnitrogen, oxygen 8 and sulfur, and again the substitutions may be the same or different. Bale aralkyl denotes an aryl group containing from 7 to 14 carbon atoms linked via a calkylene chain so that the aromatic group can carry a tandy substituent or more than one alkyl group low molecular weight; 0 alkoxy groups nitro groups 100 amino groups and/or one or more halogen atoms and the substituents are the same or different. It is preferred that aralkyl groups contain from one atom to > carbon atoms in the aliphatic moiety and “carbon atoms in the aromatic moiety.” The preferred aralkyl groups are benzyl phenethyl Vo. and phenylpropyl unless otherwise indicated. The halogen, L halogen, not otherwise mentioned, denotes fluorine, chlorine, bromine, iodine, and fluorine is preferred to chlorine or bromine, unless otherwise specified. ; Amino denotes the functional group, function NH; NH, which may carry one or two “Crgalkyl©” substituents. JH Aryl 0 or caralkyl may be the same or different. Gay for that; alkylamine for example Jd denotes methylamino ¢methylamino ethylamino Junge cethylamino amino ¢propylamino 1-methylene-ethylamino ¢1-methylene-ethylamino butylamino <butylamino 1-methylpropylamino ¢l-methylpropylamino "-methylpropylamino 2-methylpropylamino or (SEY) methylethyl yo amino .1,1-dimethylethylamino q.¢

analogously; Dialkylamino (cdialkylamino) for example (Jd) denotes dimethyl amino (s—\ “dimethyl amino” cdiethylamino “dipropylamino” dipropylamino dibutylamino sans150” di-(1-methyl) di-(I-methylethyl)amino «di-(1-methylpropyl)amino «di-(1-methylpropyl) amino - Jey ° propylamino «di-2-methylpropylamino ethylmethylamino or methylpropylamino_.bale cycloalkyl denotes a saturated or unsaturated cyclic hydrocarbon group containing from © to 9 carbon atoms carbon may carry one substituent or more of Juaii halogen atoms fluorine 0 may be the same or different from each other Preferably cyclic hydrocarbon groups containing from ? to 7 atoms carbon 00 H. Examples include cyclopropyl cyclopropyl cyclobutyl cyclopentyl cyclopentenyl cyclohexyl cyclohexenyl cycloheptyl Heptenyl cycloadrasmahan'; cycloheptadienyl ccyelooctyl yo cyclooctenyl cyclooctadienyl and nonenyl cyclononinyl heteroaryl for the purposes of the above definition denotes fale a ring consisting of five or Six members may contain oxygen, coxygen, sulfur, and/or nitrogen in the form of heteroatoms that can be combined with an aromatic ring. It is preferable for aromatic rings consisting of five or six members that contain Ye contains coxygen sulfur and/or not more than two nitrogen atoms and may be condensed with a benzo-condensed group. Examples of heterocyclic systems in particular include: <acridony! ut

A

azanaphthacenyl azacyclazinyl cazaindolyl Jd ga 31 3) cazacyclazinyl cazatriphenylenyl azaprinyl 828016 night cazepinyl <benzazapinyl benzapenesyl <benzacridinyl “benzopyranyl benzopyranonescl 1l77800m8020; benzoperatimal ¢benzonaphthyridinyl ° benzoquinolizinyl cbenzoquinolinyl benzoquinolinyl ¢benzopyronyl benzoperonisil benzyl <benzothiophenyl Jad gd Hac benzothiepinyl—iaad benzo “benzoquinolizinyl ebipyridinyl dipyridinyl ¢benzylisoquinolinyl iso quinolinyl ccarbolinyl cr polyenyl ccarbazolyl carbazolyl <caprolactamyl caprolactamyl ¢butyrolactonyl chromenopyronyl chromenopyronyl chromenopyronyl ccatechinyl 0 X hydroquinolinyl ccumaronyl coumarinyl ccumarinyl coumarinyl ¢chromonopyrany! : decahydroquinolonyl decahydroquinolonyl ¢decahydroquinolinyl dibenzazapinyl SU <diazaphenanthrenyl diazaanthracenyl dichromylenyl cdibenzothiphenyl dibenzofuranyl dibenzofuranyl dihydr and isocoumarinil «dihydrofuranyl dihydroisoquinolinyl dihydroisoquinolinyl dihydroisoquinolinyl dihydroisoquinolinyl 071 cdihydropyranyl AL dihydropyronyl AL cdihydropyridonyl dioxanthylenyl dioxanthylenyl , Diprylenyl SU cdihydrothiopyranyl fluoranyl fluoranyl flavonyl flavonyl flavanyl flavyl coenantholactamyl enantho-lactamyl 7 furanochromanyl furandionyl cfluoresceinyl fluoresceinyl furoberanyl furanyl furanyl “fiuranoquinolinyl furanoquinolinyl cfuranonyl furanyl hexa-cheteroazuleny! Mixed azolinyl cfuropyronyl furoberonyl cfuropyranyl <hydrofuranyl hydrofuranyl chexahydropyrazinoisoquinolinyl chydropyranyl hydropyranyl chydroindolyl Ja sail hydro chydrofuranonyl hydrofuranyl Yo 8.4 aq

chydropyridinyl Jie 5038 hydropyrrol aa chydropyrrolyl and quinolinyl

c<hydrothiophenyl hydrothiochromenyl <hydrothiochromenyl chydroquinolinyl cisatinyl isethinyl cindolonyl indolonyl ¢indolizinyl indolezidinyl

Isato gitell disatogenyl isobenzofurandionyl «<isobenzofurandionyl isobenzofurandionyl

<isobenzfuranyl ° isochromanyl cisochromanyl

cisoindolyl

isoquinolinyl estamsomo isoquinuclidinyl cisoquinuclidinyl lactamyl clactamyl lactonyl clactonyl maleimidyl “maleimidyl monoazabenzonaphthenyl” cpaphthalenyl naphthimidazopyridindioneyl “naphthimidazopyridindioneyl” naphthindolysine dione rather

000001121060101 ridinyl perhydroindolyl cperhydroindolyl phenanthraquinonyl “phenanthraquinonyl sphthalideisoquinolinyl cphthalimidyl phthalonyl samtam piperidinyl veo piperidonyl prolinyl para-xenyl pyranoazinyl pyranoazolylm ¢pyranoa zolyl ¢pyranopyrandionyl

pyranopyridinyl y pyranopyridinyl inocinoquinolinyl pyranoquinolinyl epiyrazolopyridinyl sin ysl J sw pyranyl Jl x epyranopyrazinyl pyridinethionyl pyridinopyridinyl Jai yu ed yu epyridinonaphthalenyl Y .epyridinyl ¢pyridocolinyl pyridoindolyl pyridopyridinyl pyridopyrimidinyl pyridopyrrolyl pyridoquinolinyl pyrrothyl a1g e rm; Jil Sg as ¢pyrrocolinyl ¢pyrrolidinyl epyrrolizidinyl pyrrolizidinyl ¢pyrrolizinyl pyrrolodioazinyl ¢pyrrolodioazinyl ¢pyrrolonyl pyrrolopyrimidinyl Yo pyrroloquinolonyl “pyrroloquinolonyl” pyrr olyl quinacridonil

Va «quinolizinyl quinolizidinyl cquinolinyl quinolinyl quinacridonyl crhodaminyl rhodamineyl quinuclidinyl cquinolonyl quinolonyl succinimidyl succinimidyl quaternary succinimidyl hydrofuranil 0:01% Tetrahydroisoquinolinyl ¢ sulpholenyl detrahydropyridinyl dtetrahydroisoquinolinyl °

Jub sig ctetrahydrothiapyranyl tetrahydrothiapiranyl ctetrahydropyridinyl quaternary ctetrahydrothipyranonyl tetrahydrothiopyranyl stetrahydrothiophenyl cthiaphenyl thiaphyl ctetronyl tetronyl ctetrahydrothipyranyl Jail yd g Ha cthiapyranyl Js} juss cthianaphthenyl cthiadecalinyl thiadecinalyl cthiachromanyl sthienopyridinyl thiazolopyridinyl thiazolopyridinyl “thiapyronyl 1 thiapyronyl sthienopyridinyl thienopyridinyl thienopyridinyl”; thiochromenyl cthienopyrrolyl thienopyrrolyl triazanthracinyl thiopyranyl thiocumarinyl thiochromenyl striazolopyridinyl < thiochromenyl striazolopyridinyl striazinoindolyl triazinoindolyl 0122880116 adenyl exathydrolyl xanthonyl “Munti_zathydrolyl exanthenyl tropanil shock 0;_xanthinyl < anthranilyl anthranilyl calloxazinyl calloxanyl cadeninyl Vo az anthranilyl cazabenzonaphthenyl cazabenzanthrenyl Jy ad cazinyl cazapurinyl azaphenoxazinyl azaphenoxazinyl cazanaphthacenyl Benzazinyl cbarbituric acid barbituric acid cazolyl azole cazoloazinyl azolo azinyl benzimidazolonyl ¢benzimidazolethionyl benzimidazolethionyl cbenzazinyl

Jud g3 wg Hu “benzisoxazolyl benzisoxazolyl” benzisothiazolyl benzisothiazolyl XY. benzodiazocinyl benzodiazocinyl benzocinnolinyl benzopyridazinyl dioxolanyl 0201001 benzodioxolanyl 5% benzothiazolyl benzothiazolyl benzothiazepinyl benzothiazepinyl benzothiazolanyl Ixazolyl “benzoxazolinonyl benzoxase and linotyl”. cbenzoxazinyl (Jy guild) cbenzoxazinyl is absorbed; Dipsidinyl racytomol <benzoxazolyl Yo a. ¢

01

“diazaphenanthrenyl diazepinyl silo0182; Diazinyl is a dibenzoxazepinel

1 10202; AL hydrobenzimbidazolyl “dihydrobenzimidazolyl”

cdihydrobenzothiazinyl dihydrooxazolyl dihydrobenzothiazolyl

azinyl hydropyridazinyl dihydropyridazinyl dihydropyrimidinyl dihydropyridazinyl

° dihydrothiazinyl dihydrothiazinyl dioxanyl dioxenyl

dioxepinyl dioxinonyl dioxinonyl dioxolanyl

dioxolonyl dioxopiperazinyl dioxopiperazinyl dipyrimidooperazinyl

dipyrimidopyrazinyl dithiolanyl cdithiolanyl dithiolenyl AL cdithiolenyl thiolyl inanomantane flavinimyl ¢flavinyl four and pyrimidinyl cfuropyrimidinyl glycocyamidinyl

Guid gig ul hexahydropyrazinois cguaniny]l guaninyl cglycocyamidinyl 0 hexahydropyridazinyl hexahydropyridazinyl <hexahydropyrazinoisoquinoliny! <hydroparazinyl hydr and para azinyl ¢hydroimidazolyl Jug aad) hydro chydantoinyl hydropyrimidinyl chydropyridazinyl hydropyridazinyl chydropyrazolyl cimidazolyl imidazolinyl chydropyrimidinyl imidazole Yazolyl 108208201 Ensedazole Benzopyrazole 101082000108201 Vo ISO ¢inosinyl indoxazolyl 040*261 indazolebenzopyrazolyl “isoxazolidinyl isocazolidinyl” isothiazolyl Jy 3 gl disoalloxazinyl cisoxazolinyl cisoxazolinonyl isoxazolinonyl meth thimetisyl <lumazinyl lumazinyl <isoxazolyl cisoxazolonyl smorpholinyl naphthymidazolyl methyluracilyl ¢methylthyminyl Y. coxathiolanyl oxathiolanyl coxathianyl coroticyl rotisyl ¢naphthimidazolyl «oxazolidiny! oxazolidinyl <oxazolidinonyl <oxazinonyl oxazolinyl oxazolinonyl oxazolinonyl oxazolidonyl coxazolyl coxazolopyrimidinyl coxazolonyl perhydropyrro loazinyl Perhydropyroloazinyl «perhydrocinnolinyl Perhydrosinolinyl Yo

q. ¢

VY

Perhydropyrrolothiazinyl Perhydropyrrolothiazinyl Perhydrothiazinonyl Perhydrothiazinonyl Pyrimidinyl: M phenazinyl phenothiazinyl phenothiazinyl phenothiazinyl esterase 100m Phenoxazonyl P-thalaazinyl ¢phthalazinyl piperazindioneyl 1082100101 Piperazinodioneyl ¢piperazinodionyl polyquinoxalinyl ¢polyquinoxalinyl pteridinyl epterinyl purinyl ¢pyrazinyl pyrazinyl pyrazolidonyl jui GAG 3) Yu ¢ Pyrazolidinyl Beraz and Levinnyl Parazolinyl Eparazolinyl Prazolopinso Even (on Azrazolyl J— 531 yu “pyrazolotriazinyl 01 epyridazinyl ¢pyridazonyl pyridazonyl” pyridopyrazinyl pyridopyrimidinyl ¢pyrimidinethionyl pyrimidionyl “pyrimidionyl Ju gad ay yu cpyrimidiny! Zepinil «pyrimidoazepinyl pyrimidopteridinyl pyrrolobenzodiazepinyl pyrrolodiazinyl epirrolopyrimidinyl quinazolidinyl Vo quinazolinonyl cquinazolinyl quinoxquinox alinyl ¢sultamyl csultinyl ¢sultonyl tetrahydrooxazolyl tetrahydrooxazolyl tetrahydropyrazinyl tetrahydropyridazinyl tetrahydropyridazinyl tetrahydroquinoxalinyl tetrahydrothiazolyl thiazolinyl ct hiazepinyl thiazinyl cthiazinyl thiazolidinonyl cthiazolidinonyl Ye thiazolidinyl cthiazolinonyl J— sid s 5 sthiazolidinyl thiazolidinonyl cthiazolyl thiazoloyl cthiazolobenzimidazolyl thiazolinyl cthiazolinyl (Dh “thyminyl) cthiazolidinonyl thienopyrimidinyl thienopyrimidinyl azolopyrimidine ctriazolopyrimidinyl uracilyl curacylyl xanthinyl exanthinyl exylitolyl cazabenzonaphthenyl benzofuroxanyl cbenzofuroxanyl benzothia yo dixyl benzothiadiazinyl benzotriazepinonyl <benzotriazepinonyl benzotriazolyl q.¢

cbenzotriazolyl benzoxadiazinyl cdioxadiazinyl dithiadazolyl dithiadazolyl dithiazolyl furazanyl furoxanyl cfuroxanyl hydrotriazolyl hydroxytriazolyl < hydroxytrizinyl coxadiazinyl coxadiazolyl <oxadiazolyl ° coxathiazinonyl coxatriazolyl pentazinyl ¢pentazolyl epentazinyl polyoxadiazol yl ¢sydonyl tetraoxanyl ctetraoxanyl detrazepinyl tetra Jb dtetrazinyl tetrazoyl ctetrazolyl thiadiazinyl Joy thiadiazolinyl thiadiazolinyl 201; Thia Dioxazenyl 21H 18010 »; Thia Thilante Lb cthiatriazinyl Jif Ve Triazolyl cthiatriazolyl Thia Triazolyl 1208201 Triazolinyl ctriazepiny! Triazinoindolyl 012210010001 Triazolinyl “triaziny! Triazolyl, ctriazolyl, trioxanyl TO ctrioxanyl ctriphenodioxazinyl triphenodioxazinyl Ji J Sl «triphenodithiazinyl triphenodithiazepinyl ctrithiadiazepinyl ctrithianyl or trioxolanyl yo-oxolanyl compounds of this type are now known from a German reference entitled German Offenlegungsscrift (German Offenlegungsscrift No. Khart) + Tekla and as a result of their effect as inhibitors of the exchange of Nat and HF ions in the cell; Such compounds may be used as active A25 ingredients for pharmaceutical compositions or say used as intermediate products for the preparation of such active ingredients. The compounds according to the invention are effective against arrhythmias that occur; For example; At 48 oxygen from «e0mt. It may also be used for diseases related to ischaemia (such as cardiac, cerebral, and gastrointestinal conditions - such as yo-thrombosis / mesenteric thrombosis/embolism, pulmonary and schizophrenia) q.¢

VE ischaemia of the skeletal muscle (5 535 ¢ischaemia of the liver and renal ischaemia of the liver) including such diseases as for example coronary heart disease. of the skeletal muscle cangina pectoris cardiac infarct coronary heart disease ventricular cangina stable pectoris stable angina heart failure ¢sub-ventricular arrhythmias carrhythmias ° «bypass operations in support of bypass surgeries AX is used ¢— cardiac insufficiency, to support surgeries that require copen heart surgery, to support open-heart surgery, embolism, and heart transplants in which the blood supply to the heart is intermittent, and to support acute or acute heart transplantation kidney failure pulmonary circulation cerebral insufficiency chronic kidney insufficiency chronic renal insufficiency 1 by reperfusion and cerebral infarct damage and disorders Vascular occlusions clearing vascular occlusions to areas of the brain after acute and chronic brain removal. In this statement, compounds may be used for bleeding disorders Ady such as thrombolytic agents for the aforementioned Als clot as well in conjunction with urokinase factors and streptokinase t-PA in tissues Ome Vo angina attack During reperfusion of the withered heart (for example after a seizure) irreversible damage (cardiac infarct or thoracic angina pectoris) may occur to the 85 cardiomyocytes in the injured area. The compounds according to the invention have in Cases like this. “sal from” ee “among other things protective activity protective activity of the heart is among the main matters transplants and prevention of damage to transplanted organs ve or Kidney or kidney liver should also be considered For the treatment of ailments (eg to protect a transplanted organ such as a liver before, during and after implantation, and during storage of organs for transplantation) that may clung or lung or heart have an effect drugs occur in connection with the transplanted organ. They are drugs in the heart and in peripheral blood vessels angioplastic surgery during angioplasty surgery Us .peripheral blood vessels Yo

Vo diabetic primary and diabetic nephropathy AD} high pressure (A) in the cell; therefore, the sodium proton nephropathy compounds of the invention are suitable as inhibitors of this exchange to prevent these diseases. Tid of the invention in addition to This has an effective inhibitory effect on the Gy branching, and the compounds are distinguished. Accordingly, the compounds are considered useful drugs in treating the proliferation of cells (or secondary) and may be used as drugs against (Lei) diseases in which the cell branching plays a role. Or, for example, benign tumors or benign tumors, cancer, organ cancer, atherosclerosis 5, prostate hypertrophy, late complications, fibrotic diseases, fibrotic diseases, hyperplasia, and hypertrophy -diabetes. for diabetes ye and moreover; Compounds of this type are known to have a favorable effect on serum levels of lipoproteins. Serum lipoproteins have now been found surprisingly well; that compounds of general formula 1 possess the advantage of knowledge from prior art; Not only is benzoylguanidine superior to oral benzoylguanidine derivatives that are unexpectedly more effective, but they are also considered suitable for parenteral administration. Administration of General Formula 1 in the form of an injectable aqueous solution iy The active substances may be used or Jal intravenous for intravenous administration (eg aqueous injectable solution ctablets) or as subcutaneous intramuscular transdermal tablets for intradermal use plasters Plasters for ointments ¢suppositories Y. .nasal spray Through the lungs or nasal spray aerosols for inhalation Aerosols for inhalation The content of the active substance in the tablet or suppository ranges between © and 7800 mg; preferably carla 01 and 01 0086 Single dose between dose and for inhalation 0 mg 0 1 5 00 single dose between ¢ parenteral injection and © 17 mg for non-enteric injection between 8.4

1,00 mg; Preferably between 0.8 and 50 mg. The above doses may be given several times a day as required. The following are some examples of pharmaceutical preparations that contain the active substance: Active substance tablets in general formula (1) 0 mg magnesium stearate 0 mg Las corn starch 0 corn lactose $3SY Polyvinylpyrrolidone 1.1 mg 0 The solution can be sterilized by standard methods Solution for injection Active ingredient with general formula I 8 g Sodium chloride +,Y Sodium chloride g Water for injection Sufficient quantity to bring the volume Total 0 ml Aqueous solution for nasal administration or inhalation Active substance in general form (1) “rh gm Sodium chloride +d Sodium chloride gm Benzalkonium chloride pra 6,61 Benzalkonium chloride Purified water Sufficient quantity to bring the volume 0 SS ml and the aforementioned solution is considered Lie for administration through the nose in a spray, or it is considered Wide for administration in the lungs when used in contact with an instrument that produces an aerosol solution having a particle size of 1, preferably between ? and 6. micrometer m.m

Rolling capsules for inhalation Compounds of the general formula 1 are filled in capsules of hard gelatin (A capsules) in miniature form (the particle size ranges mainly between ? Ts micrometers); softening carriers may be added, Jie lactose and inhaled by conventional apparatus ° to inhale the powder 0 and fill between 01.7 and 70 mg of the active substance in general form 1 and from zero to pie Eo of lactose 6 in each capsule, eg. 1 1 part of soya lecithin 01 part of a propellant gas mixture A sufficient amount until the amount reaches 001 part, and it is preferable to transfer the product to aerosol containers that have a calibration valve 8; and drain Each spray is a dose of 5 mg.For further doses in the specified range 1 ¢ Use preparations containing appropriately larger or smaller proportions of the active ingredient. fuming hydrochloric acid 01g sodium pyrosulphite 4.10g A mixture of equal parts cetyl alcohol and stearyl alcohol: stearyl alcohol 0 3 white vaseline ©g synthetic bergamot oil 1/6 ; gram distilled water sufficient quantity until the total volume reaches 100 and the ingredients are treated in the usual manner to form an ointment. 8.8

Ya

of the invention in general from the prior technique; Thus, Gay knows the methods of producing compounds, for example: Aula) Compounds can be obtained according to the invention by the method

Aol by reaction of 4-(1-piperazinyl)-7-trifluoromethylbenzoic acid esters 11 with the general formula piperazinyl)-3-trifluoromethylbenzoic acid esters ¥ and F OL a” 0 (1) 111 with a compound of general formula (1m) R,C(O)Q may bear a nitrogen substitute leaving group where © denotes an easily removable group Preferably carbonyl cadjuvants May be in the presence of auxiliaries cpiperazine nitrogen Piperazine Ve benzoic acid The resulting benzoic acid derivative is “carbonyldiimidazole diimidazole”

IV in the general form

Fg Q 1 1 baker 07 Ne Oo (Iv) preferably canhydrous dimethylformamide which was suspended in a suitable solvent 8; Preferably anhydrous Vo preferably cbase hydride and mixed with a mixture of solution or suspension of cdimethylformamide base

Va masked anhydrous solvent; Preferably dimethyl formamide (sodium hydride sodium) Preferably guanidine hydrochloride 06M0108171100 with guanidine salt - and the reaction product is separated. guanidine hydrochloride The present invention is explained by the following examples: For more details all Description ALAN) methyl 4-fluoro-3-trifluoromethyl-benzoate -fluoro-?-trifluoromethyl-benzoate methyl ¢ from acid; -Fluoro-7-(trifluoro) (mmole mmol 171) g YO, E Mixing methanol ml of methanol YOu in methylated 4-fluoro-3-(trifluoromethyl) benzoic acid )-benzoic mL of .8001; while cooling with ice; at a temperature of µm (°C) Wh with 0 heat the reaction mixture with reflux for ¥ hours 0 min. After adding all ingredients Yo through an additional ambient temperature concentrate. The reaction solution was cooled to ambient temperature 10 ml of diethyl 001 oily residue by evaporation in a vacuum. The saturated oily concentrate was dissolved and then again with NaHCO, It was extracted using water and a solution of diethylether ether, magnesium sulphate, and water. The organic phases were dried after mixing them over magnesium sulfate Vo and concentrated by evaporation in vacuum. methyl 4-(4-benzyl-1-fluoromethyl-benzoate Y= (da) we 1-lyspene-4(-4 piperazinyl)-3-trifluoromethyl-benzoate

J fie from; -Fluoro-7-trifluoromethyl-benzoate (Use mm TY.) g Y Dissolve Ye mL of dimethyl sulfoxide 01 in methyl 4-fluoro-3-trifluoromethly-benzoat of 7<-Benzyl (Use dry and mix with 0.00 g (71.0 mmol) (DMSO) dimethylsulphoxide potassium carbonate (TY, 0) g £,Y0 5 N-benzylpiperazine piperazine ‎Lag. m Av hours at a temperature of VY and the mixture was stirred for a period of potassium carbonate cooling; Pour the reaction mixture into 709 mL of water and extract three times with acetate VO 8.4

’ ethyl acetate each time. The organic phases were washed after mixing them with water and a saturated sodium chloride solution. It was dried over magnesium sulphate and removed by distillation in a vacuum. The concentrate was impregnated on silica gel using a mixture of

ethyl acetate and p-- heptane .n-heptane 0 yield YAY g of compound (production rate-(IFT V)-¢-piperazinyl)-EX fluoromethyl- methyl 4-(1-piperazinyl)-3- trifluoromethyl-benzoate dissolve 7 g OFT mmol) of 4-(4-benzyl-NT = (J ow) fluoromethyl-benzoate Methyl 4-(4-benzyl-1-piperazinyl)-3-trifluoromethyl-benzoate in 5000 ml 1 of methanol and mixed with ?gm of palladium on a charcoal pad and hydrogenated to 0 throughout A time period of 1.4 hours at a temperature of 0 L, which induces a pressure of hydrogen of ¾ bar, and the solution is filtered by suction over a filter agent of the celite type. © CELITE (Registered Trademark) and removed by distillation in vacuum. 1 yield 15,808 g of compound (yield-(7a) general method of binding ;-(1-piperazinyl)-7-tri Fluoromethyl-benzoate (methyl 4-01- Jie piperazinyl)-3-trifluoromethy-benzoate with benzoic acids oil mmol of corresponding carboxylic acid in Vo ml of tetrahydrofuran (THF) tetrahydrofuran drained and mixed in the presence of 0 tear gas (35 protectire) at zero degrees Celsius with pale 800© (mmol) of carbonyldiimidazole and stirred for two hours at ambient temperature ( about ° (oY) then add 584 g (© mmol) of ;-(1-piperazinyl)-7-trifluoromethyl-benzoate methyl 4-(I-piperazinyl)-3-trifluoromethyl-benzoate and stir Mix for another 17 hours. The solution was evaporated until it reached dryness in a vacuum and dissolved in wethyl acetate, and after vo washing with a saturated NaHCO solution, a saturated NaCl solution, and water, the organic phases were dried 8.4.

in crystallisation above ,11850 and concentrated by evaporation in a vacuum. And after crystallization, the organic phases, by voiling with a suitable solvent; A suitable solvent or chromatography on silica gel obtained the following compounds. 4-(;-(7-methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-methylbenzoate (1) methyl 4-(4-(3-methoxyphenylcarbonyl)-1-piperazinyl)- 3-trifluoromethyl-benzoate ° n- p-heptane ethyl acetate Column chromatography: Use a mixture of ethyl acetate (0:7) in proportion heptane (ZA = z wy) (modified 4-(;-(7-pyrolyl carbonyl)-1-piperazinyl)-”- trifluoromethyl-benzoate (Y) methyl 4-( 4-(2-) pyrrolylcarbonyl)-l-piperazinyl)-3-triflucromethyl-benzoate 01 methanol Crystallization was carried out in methanol (Ivo (production rate- 109 melting point) 4-(?-(; -fluorophenylcarbonyl)- 1-piperazinyl)-?- trifluoromethyl-benzoate (7) methyl 4-(4-( 4-fluorophenylcarbonyl)-1-piperazinyi)-3 -trifluoromethyl-benzoate Vo n- and p-heptane ethyl acetate Column chromatography: use a mixture of ethyl acetate (0:7) in proportion heptane (AVY (production rate-phenylcarbonyl)-1-piperazinyl)-?-trifluoromethyl-methylbenzoate (eS mY) =) (?) methyl 4-) 4-(2-methoxyphenylcarbonyl)-1-piperazinyl)-3 -trifluoromethyl-benzoate XY. p-heptane ethyl acetate column chromatography: use a mixture of ethyl acetate: (7) 7979 (production rate- ;-(©-(©-trifluoromethylphenylcarbonyl)-1-piperazinyl) -*-trifluoromethyl- (0) 8.4

YY methyl 4-(4-(3-trifluoromethylphenylcarbonyl)-1-piperazinyl)-3- trifluoromethyl-benzoate n-p-heptane ethyl acetate Columnar chromatography: use a mixture of ethyl acetate (0:7) (Its ratio is heptane) 787 (production rate - 4-methyl (;-phenylcarbonyl-1-piperazinyl)-*-trifluoromethyl-methyl benzoate (1) 4-(4-phenylcarbonyl-1-piperazinyl) )-3-trifluoromethyl-benzoate n- and p-heptane ethyl acetate Columnar chromatography: Use a mixture of ethyl acetate ( ) heptane (production rate - d0

Jal 4-(;-(7-furylcarbonyl)-1-piperazinyl)-7-trifluoromethyl-benzoate ) ( methyl 4-(4-(2-furylcarbonyl)-1 -piperazinyl)-3-trifluoromethyl- benzoate n--heptane ethyl acetate Columnar chromatography: Use a mixture of ethyl acetate (0:7) in the proportion of heptane

AL=z uy! Jaa) yo 4-(;-(“-methylphenylcarbonyl)-1-piperazinyl)-”-trifluoromethyl-methyl benzoate (A) methyl 4-) 4-(3-methylphenylcarbonyl)-1 -piperazinyl) -3-trifluoromethyl-benzoate n- and p-heptane ethyl acetate Column chromatography: Use a mixture of ethyl acetate (0: Y) 4%. heptane (Ava (Rate- Ye phenylcarbonyl)-1-piperazinyl)-?-trifluoromethyl-benzoate (Lyreb-1(-4)-©(-4 (9) methyl 4-) 4 -( 4-(1-pyrryl)phenylcarbonyl)- 1-piperazinyl)-3-trifluoromethyl- methyl benzoate n- heptane ethyl acetate JOY! Column chromatography: Use a mixture of acetate (): Y) attributed to heptane Yo a. ¢

YY

LAY (production rate- 4-(4-(?-pyridylcarbonyl)-1-piperazinyl)-*-trifluoromethyl-benzoate, methyl 4-(4-(2-pyridylcarbonyl)- 1-piperazinyl)-3-triftluoromethyl-benzoate n- and p-heptane ethyl acetate JY! Columnar chromatography: A mixture of (0:7) acetate (0:7) was used in the ratio of heptane ° (AVY) (production rate - from Methyl carbonate compounds, acyl guanidines, a general method for the preparation of the corresponding acyl guanidine compounds, methyl carbonates, its concentration is 7700 in white oil, NaH (mmol) from 1 77.7 (5.05 g 17.109 wash) DMF was added in ml of Yoo and clarified. Ether was added twice using ether 0 in small amounts with guanidine hydrochloride (1 mmol) of guanidine hydrochloride (1 g) mmol of THY ester stirring In the presence of a buffer gas, and after stirring for one hour, the contrast was added and the solution was stirred for an additional two hours at a temperature of methyl ester, then the reaction mixture was left to cool to the ambient temperature, filtered and concentrated at about 1171 C 0 By elution with a suitable solvent, silica, by evaporation in a vacuum, and after chromatography on silica gel or other acids, ethereal hydrochloric acid, and transformation using aromatic hydrochloric acid, the following compounds were obtained: Alia, which is pharmaceutically acceptable to salts, for example The first prepared hydrochloride 4-(4-(;-methoxy_phenylcarbonyl)-1-piperazinyl)-7-trifluoro 4-(4-(4-Methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl- methyl- 7 benzoylguanidine-hydrochloride

Ye

FE

NE;

F i

H

NH

Set H A l" x HCl

Lg 0 of 4-(4?-(*-methoxyphenylcarbonyl)-1-piperazinyl)-?-trifluoromethyl-benzoate methy! 4-(4-(3-methoxyphenylcarbonyl)-1-piperazinyl)-3 trifluoromethyl-benzoate methyl methanol and ethyl acetate column chromatography: use a mixture of ethyl acetate

V:0 °) AVY (production rate - 001 m) Melting point: more than (base shot) £00 = "(HAM)(AL) q: (spectrum of the second example) 4-(4-(?-pyrrolyl.carbonyl)-1-piperazinyl)-?-trifluor.methyl-benzoyl ses 0 4-(4-(2-Pyrrolyl carbonyl)-1-piperaziny!)-3 -trifluoromethyl-guanidine-methanesulphonate benzoylguanidine-methanesulphonate

F0

NHz

F i 4 1 1 ver

N

N

6

Jie of 4-(4-(?-pyrrolylcarbonyl)-1-piperazinyl-*-trifluoromethyl-benzoate methyl 4-(4-(2-pyrrolylcarbonyl)-1 -piperazinyl)-3-trifluoromethyl-benzoate Vo

Av¢

Column chromatography: Use a mixture of ethyl acetate and methanol (0:9) (production rate - 471) Melting point: 3 "m 0 TK: (HM) < 0 (base shot ) The third example prepared 4-(4-(;?-fluoro-phenylcarbonyl)-1-piperazinyl)-7-trifluoromethyl-benzoylguanidine-methane (Fluoropheny1carbonyl)-1-piperazinyl)-3-trifluoromethyl- -4)-4)-4 benzoylguanidine-methanesulphonate FgO

NH, 8 — - NH 0 x CH3SOsH but LL 0 yo of 4-(4-(©-fluorophenylcarbonyl)-1-piperazinyl)-"-trifluoromethyl-methyl benzoate 4-(4-methyl) (4-fluoropheny! carbonyl)-1-piperazinyl)-3 -trifluoromethyl-benzoate in the ratio of methanol and methanol ethyl acetate Jay! Column chromatography: Use a mixture of (2:1) acetate (66 (production rate- yo m 10 melting point: 78; (base shot) ="(HHM) dd ba

Fourth example prepared hydrochloride 4-(4?-(7-methoxy_phenylcarbonyl)-1-piperazinyl)-"-trifluoromethyl-benzoylguanidine 4-(4-(2-methoxyphenylcarbonyl)-1-piperazinyl)-3- trifluoromethyl- benzoylguanidine-hydrochloride Bg 0 NH; foosy NH N a 8 \ of 4-(;-(7-methoxyphenylcarbonyl)-1-piperazinyl)-7 -Trifluoromethyl-methyl benzoate (methyl 4-) 4-(2-methoxyphenylcarbonyl)-1-piperazinyl)-3 -trifluoromethyl-benzoate Column chromatography: Use a mixture of ethyl acetate and methanol (percentage) 0 (2:1) (production rate - (AVY) Melting point: 07C (decomposes) TAC: (8+24)” <1©; (shot base) Example V prepared DOTY hydrochloride) Fluoro methylphenylcarbonyl)-1-piperazinyl)-?-trifluoromethyl-benzoylguanidine 4-(4-(3-trifluoromethylphenylcarbonyl)-1-piperazinyl)-3- trifluoromethyl-benzoylguanidine-hydrochloride

F rv F > 1 NE; . 0 x HCY for “ F, F a from FY)-E)-E ternary fe post phenylcarbonyl)-1-piperazinyl)-”- GE fluoromethyl-benzoate methyl 4-(4-(3-trifluoromethylphenylcarbonyl)-1-piperazinyl)- « all 3-trifluoromethyl-benzoate ° Columnar chromatography: Use a mixture of ethyl acetate and methanol (1:2) ( (production rate - 775) Melting point Yeo: M (decomposes) Tac: EAA = "(HM) (base shot) Ve Example VI prepared hydrochloride 4-4 ATs oar V diss dam fluoromethyl - Benzoylguanidine 4-(4-Phenylcarbonyl-1 _piperazinyl)-3-trifluoromethyl-benzoylguanidine- hydrochloride Fg 0 NH, — 1 NH 1 7" © to N 0 Gee 4-(;-phenylcarbonyl-1-piperazinyl)-*- trifluoromethyl-benzoate methyl 4(-4 methyl phenylcarbonyl-1-piperazinyl)-3 -trifluoromethyl-benzoate ¢.

Ya

Its ratio is methanol and methanol ethyl acetate Columnar chromatography: use a mixture of ethyl acetate (2:1) (418 = z wy) (rate 11 C Melting point: (base shot) £Y = ')+24( tc: © Example Seven Prepare 4-(;?-(7-furylcarbonyl)-1-piperazinyl)-7-trifluoromethyl-benzoylguanidine- 4- 4-(2 -furylcarbonyl)- 1-piperazinyl)-3-trifluoromethyl-benzoylguanidine- methanesulphonate

F0

NH;

NH

8 N

J x CH3SOsH

N. a 0 trifluoromethyl-methyl-benzoate -*-)linisarbib-1-(linoprec dos) from methyl 4-) 4-(2-furylcarbonyl)-1-piperazinyl)-3 -trifluoromethyl-benzoate ether Crystallized in ether (719) (production rate - melting point: 0090°C (decomposes) vo i k: (11+24)” < 10? (base shot) a. ¢

Ya 8th example methyl-benzoyl ssh tri-7-(linezarbib-1-)linoprec 4-(4-(©-methylphenyl) as 4-( 4-(3-methylphenylcarbonyl)-1-piperaziny1) -3-trifluoromethyl-guanidine-methanesulphonate benzoylguanidine-methanesulphonate

Fp 0 1 [8 8 4

NH

0 l : l x bort 0 l of 4-(;-(*-methylphenylcarbonyl)-1-piperazinyl)-7- trifluoromethyl-methyl benzoate methyl 4-( 4-3 -methylphenylcarbonyl)- 1-piperazinyl)-3 -trifluoromethyl-benzoate ethyl acetate and ethyl methanol The crystallization was carried out in a mixture of methanol (AV) (production rate - melting point: 1954 C) 0 tc: (mahjir) <4,7; (talq base) The ninth example is fluoromethyl- tertiary-?-(linizarbib-1-(linuprec linaf_(liliurib-1)-©)-4 (-4 as 4-(4-(4-(1-Pyrrolyl)phenylcarbonyl)-1-piperazinyl)- 3-trifluoromethyl-benzoylguanidine-dimethylsulphonate yo a.¢

Fr 0 NH; SE F — H > x2 CH,SO,H for” 0 of 4-(?-(?-(1-pyryl)phenylcarbonyl)-1- Piperazinyl)-*- trifluoromethyl-methyl benzoate methyl 4-(4-( 4-(1-pyrryl)phenylcarbonyl)-1 -piperazinyl)-3-trifluoromethyl-benzoate The crystallization was carried out in methanol 0 (production rate- (ZEN) Melting point: 1007 C (decomposes) la k: £AO = (HM) (base shot) Example 10 prepared 4-(4-("-pyridyl carbonyl)- 1-Piperazinyl)-7-Trifluoromethyl-benzoyl Yo guanidine-Dimethanesulphonate 4-(4-(2-pyridylcarbony1)-1-piperazinyl)-3-trifluoromethyl- benzoylguanidine-dimethanesulphonate Fg 0 NH, L : NH ZN with timing 2 x 2 | . Wa N : 0 oe 4-(;-(7-pyridylcarbonyl)-1-piperazinyl) -7- ssl DB methyl-benzoate methyl methyl 4-( 4-(2-pyridylcarbonyl)-1 -piperazinyl)-3-trifluoromethyl-benzoate 8.8 vy percentage of methanol and methanol ethyl acetate column chromatography: Use a mixture of ethyl acetate (0:9) 77 4 (production rate-m (decomposes) 111) Melting point: tc: (concrete) < 17; (shot base) oo Pharmacological data human intestinal cancer and Na'11 in human intestinal cancer cells. Inhibiting the exchange between ions: (HT-29) cells at a growth medium temperature of 111-29 cells in an incubated growth medium with a concentration of 0. After a period of time ranging from * to 0 days, COp was removed, amounting to 0, using 0 (Suda dye, concentration of 5,000 microns BCECF-AM — growth medium, cells were washed, and pH-susceptible bacilli) at a temperature Choline was obtained without fluorescent dye for a minute using the following medium: Choline Chloride Fo©©. The cells were washed and acidified after 1 milliliter of MgCl concentration, 01 milliliter of concentration of 10 milliliter MgCl; 103.01 Its concentration is 68

HEPES © millimerial concentration and glucose is millimolecular; Glucose VA Concentration CaCly Molecular; Vo

V,0 with a concentration of 10 mM at a pH of CO, the cells were washed for minutes of incubation at a temperature of 77 C without 1 and after its concentration of choline chloride and incubated for minutes in a washing medium: consisting of: Choline Chloride CaCl, mM;1 mM MgCl; 1601 mM concentration © 0 mM YO concentration MOPS mM; Glucose 06 concentration #*mM VAY .7, 6 at pH of test with test compound control medium, wash medium removed and mM control medium added; Its concentration is 160 mm © VY with or without NaCl It has the following composition: compound glucose mM; VA glucose, mM CaCl; 1 mM MgCl; 0.7, 10 mM Mg, at pH MOPS, © mM and ve vy were measured as CO. ; without a TY and the cells were incubated for ; minutes at a temperature of BCECF and measured the fluorescence of the dye (YY CytoFluor) using a fluorometer (CytoFluor 1/0 excitation wavelengths pH) and 4460 nm (not susceptible to pH) and at the emission wavelength cytoplasmic pH The cytoplasmic pH was calculated as 0.0 nm OY emission wavelength ° from the fluorescence ratios at the two wavelengths £40 and 4460 nm. External acidity, fluorescent signal, by measuring the fluorescent signal, nigericin, and internal acidity, using nigericin —— WSSS 780/01 mol L. Example: Inhibitory concentration of AD1B YA L ,.A ¢ oo YY°

YY: 7 oe A 0,1 7 9 \ 0 The compounds according to the invention are also surprisingly bioavailable Ve oral and long half-lives after oral administration Good tan bioavailability properties that make them exceptionally suitable For oral use. A 5 administration Pharmacokinetic data: Pharmacokinetic data

Call. gm (unstarved) for the AO tests. Male rats weighing about intravenously Jal were used to give Y acidified acidified Se substances in \o solution and orally. /kg for 7.8 cyl. Single large volumes (8 mg/kg intramuscularly at a dose of (?.ml/100g) were injected or given in the caudal vein orally) into the caudal vein and the solutions were analyzed. 0. g) Yoo [Ja \ ) inside the stomach in a dose of cansular through a bronchiole 4.4

YY

given to confirm the dose given. Parts amounting to 4.0 ml of blood were withdrawn from the venous plexus of short-term halothane anesthesia behind the eye pocket under venous plexus anesthesia for the G85 heparinised glass capillaries using glass capillary tubes treated with the following heparin: ; One hour; Two hours; ; hours; Yo minutes; Vo (© Gils) Vein: Jala after administration 0 hours; A lela 1

A cleat One hour; two hours; Hours: 11 hours after oral administration: hour. The samples were analyzed by liquid-from-liquid extraction using an internal standard coupled HPLC reversed phase plasma extracts electrospray tandem mass spectrometer. Electrophoresis and pharmacokinetic data were determined from the corresponding plasma concentrations by means of PLA analysis

Heinzel, (see article on TopFit by J. Heinzel Using pods using the Vo TopFit program

TopFit 2.0--) Reference Thomann, P. Woloszezak, R. R. and Loszczak, “G system for the PC “data analysis “Pharmacokinetic and pharmacodynamic” (New York, Jena, Stuttgart, Gustav Fischer Verlag, 17 m). Y. Example Fluorescence Half-life (intravenous) Half-life (oral) 8.6 VY iy Y 0,¢ 91 except Y for 8 oA °

Claims (1)

Ye Claims I is a compound of formula 4thre0: ? =) 1 where is Hm NH; 9 0 where: ¢ «Cp g-alkyl represents an alkyl-ene group Ry ° polysubstituted or carrying one or more substituents unsubstituted aryl aryl 1 dc jie or unbranched branched Cy 4-alkyl y SY group (ye monosubstituted for) and “myl-y©” branched or unbranched; Cra mS SI ic ganas cunbranched A group of different or different alkyl identical may carry one or more identical substituents NH, a trifluoromethyl group© aralkyl; aryl or aralkyl groups Cus 01 or a nitro cyanophotoid halogen; a strifluoromethyl nitro hydroxy group 1 or ¢ halogen Yo aryl one or more in the aryl molecular structure Sn aryla without substituents or bearing a branched asl or non-Cpy-alkyl yen Jd of an alkyl partial structure group and/or alkyl Ve NH, branched or unbranched; branched Calkoxy group; 7© alkoxy group may carry one or more identical or different alkylamine substituents of the parent; 1 “trifluoromethyl trifluoromethyl group aralkyl aryl C or aralkyl groups WY or tautomer or stereoisomer halogen or nitro halogen or cyano-nitro group VA Ae Yo .pharmaceutically acceptable salt V9 1 Compound with the formula —Y 1 9 0 NH; 7 1 NH; Nr for 2 0 where: ¢ carries phenyl or an unsubstituted phenyl ring represents a phenyl ring devoid of substituents ©: ° trifluoromethyl cmethyl fluorine atom From a Shy fluorine atom, ¢pyrrolyl or a de ganal trifluoromethyl pyrrolyl group forms one of the following groups: A N 0 N a ys , OT { . Sy ££ : LZ or its pharmaceutically acceptable salts. P tautomer or stereoisomer 4-(;-(7-pyrryl carbonyl)-1-piperazinyl)-7-trifluoromethyl-benzoylguaidine- -" 1 4-(4-(2-Pyrrolylcarbonyl)-1-piperaziny!)-3-trifluoromethyl- Oita Y sulfones or its acceptable salts tautomer or stereoisomer benzoylguanidine-methanesulphonate ,. Wana ¢ . ¢ ¢— 4-(:- fluorophenyl (Y= (di ow V (diss) fluoromethyl-benzoyl Y guanidine-methane sulfate) 4-(4-(4-fluoropheny 1 carbonyl)-1-piperazinyl) )-3- trifluoromethyl-benzoylguanidine-methanesulphonate 1 or a tautomer or ¢ its pharmaceutically acceptable salts. 1 0—Process for preparing a compound of I general formula Fp 0 NH; Y F == NH : 8 L by 0 Cua The ;-(1-piperazinyl)-"-trifluoromethylbenzoic acid ester is reacted with ;-(1-(1-piperazinyl)-"-trifluoromethylbenzoic-4.)0-piperazinyl)-3-trifluoromethylbenzoic acid ester ° in the general form [ Fp 0 7 8 Son Croe-Alleyl 1 0 © y v )0 A reacts with a compound of the general form (111) Yv (tm) R,C(0)Q 9 and the cleaving group acid derivative is suspended where © denotes an easily removable group ye and may be in the presence of carbonyl IV resulting in the general formula benzoic acid derivative 11 benzoic acid suitable; Then mix with a mixture of ude in ccarbonyldiimidazole VY “guanidine salt” with base guanidine salt from base 1 0 or suspension solution 7 solution where: reaction product Then the product is separated Reaction Vi «Crgalkyl represents an alkyl-z group ©: Vo Craalkyl Crm JS An aryl is free of substituents or carries one or more substituents from group 8, branched or unbranched; Al-Koxy Group-...0 «« Salalah-. branched or unbranched; VY Cre 0.” may carry one or more identical or different NH alkyl substituents, e.g. a trifluoromethyl aryl group or aracyl groups; Trifluoromethyl group alkyl V4 or chalogen or halogen nitro nitro group ccyano cyano chydroxy 7 is devoid of substituents or carries one or more substituents in the molecular structure calkylaryl alkyl aryl "1 branched nuclei Crm OS) de sana of alkyl to aryl and/or alkyl partial structure YY branched or unbranched Cpy-alkoxy or unbranched; alkoxy-b group YY may bear one or more substituents Two identical or different substitutes of NH, ve group caralkyl aryl trifluoromethyl group or aralkyl groups Crpralieyl Cugm JY Yo halogen or nitro halogen or nitro group “cyano” trifluoromethyl 71 compound includes on a compound Pharmaceutically acceptable carrier = 1 of a claimant (0 7 © or ; Gay of pharmaceutically acceptable carrier of formula Y .pharmaceutical preparation 7 resulting from tissue damage reduction or Limiting treatment The method for treating 1-1 of a patient to a therapeutic amount includes giving a therapeutic amount of ischaemia withered Y YA 7 suffers from the wither of the compound with the formula of according to claim 1 − 7 © or 4.—A 1 method Bag of claim 0 Cua Base 6 is sodium hydride .sodium hydride Y 1 4- Method G5 of claimant A where sodium hydride is Y ¥ anhydrous solvent 1 . = method ( ad for claimant 8( Cua the anhydrous solvent is Y dimethyl formamide -11 1 method Gay for claimant 0” where base is solvent Anhydrous solvent 7 ft. VY 1 Method according to claim 01 where the anhydrous solvent is Y dimethyl formamide ST Method according to claim 60 where the salt is Guanidine cquanidine salt is Y guanidine hydrochloride .guanidine hydrochloride : Cua © Method according to claim 6-1 Ry Y represents an unsubstituted phenyl ring or a phenyl ring Sha of Y 33 fluorine methyl Jie dc sana fluorine a trifluoromethyl ¢ carries a methoxy group or a 3-pyrryl group, or is one of the following groups: 4.4 N N Fl 3 OF = ’ SLE A 1 - Method Ba of claim; 1 where the base is sodium hydride .sodium hydride Y 1 - Method Big of claimant 0 11 where sodium hydride Y is an anhydrous solvent Ale -11 .1 Method Ga For the claim ON where the anhydrous solvent is Y dimethyl formamide .dimethyl formam ide = A 1 method according to the claim dua (VE) base 86 is an anhydrous solvent .anhydrous solvent Y 1 4- The method according to claim VA where the anhydrous solvent is Y dimethylformamide .dimethy! formam ide 0-1 The method according to the claim NE where the guanidine salt is Y is guanidine hydrochloride. ‎A.¢